AT5026U1 - METHOD FOR PRODUCING CITALOPRAM - Google Patents

Abstract

A process for the preparation of citalopram is disclosed which comprises converting a compound of formula (VIII), wherein Z is halogen, to a compound of formula (IV), followed by converting the compound of formula (IV) to citalopram. Methods for making the compound of formula (IV) are also disclosed.

Description

AT 005 026 Ul

The present invention relates to a process for the preparation of the well-known antidepressant drug citalopram, 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile, process for the preparation of the Intermediate stages used by Citalopram and procedures for converting the intermediate stages to citalopram. BACKGROUND OF THE INVENTION:

Citalopram is a well-known antidepressant drug that has been commercially available for several years and has the following structure:

It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, which has 2 AT 005 026 Ul corresponding antidepressant activities. The antidepressant activity of the compound has been reported in various publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. &Amp; Biol. Psychiat. 1982, 6, 277-295, and A. Gravem, Acta Psychiatr. Scand. 1987, 75, 478-486. The compound has also been disclosed to show effects in the treatment of dementia and cerebrovascular disorders (EP-A-0 474 580).

Citalopram was first disclosed in DE 26 57 013, corresponding to US Pat. No. 4,136,193. This patent publication describes the production of citalopram by one process and outlines another process that can be used to produce citalopram.

According to the process described, the corresponding 1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofuran carbonitrile is reacted with 3 - (Ν, Ν-dimethylamino) propyl chloride in the presence of methylsulfinyl methide as the condensing agent.

The starting material was prepared from the corresponding 5-bromo derivative by reaction with copper (I) cyanide.

According to the procedure, which is only outlined in general terms, by ring-closing the compound, citalopram can:

in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with copper (I) - 3 AT 005 026 Ul cyanide can be obtained. The starting material of formula (II) is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenylmagnesium chloride or N, N-dimethylaminopropylmagnesium chloride.

A new and surprising method and an intermediate for the production of citalopram have been described in US Pat. No. 4,650,884, according to which an intermediate of formula (III)

is subjected to a ring closure reaction by dehydration with concentrated sulfuric acid to obtain citalopram. The intermediate of formula (III) was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4 - fluorophenyl magnesium halide or N, N-dimethylaminopropyl magnesium halide.

Further methods are disclosed in International Patent Application Nos. WO98 / 019511, WO98 / 019512 and WO98 / 019513. WO98 / 019512 and WO98 / 019513 relate to processes in which a 5-amino, 5-alkoxycarbonyl or 5- (sec-aminocarbonyl) phthalide is used in two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative corresponding 5-cyano-4 AT 005 026 Ul

Connection, i.e. Citalopram. International patent application No. WO98 / 019511 discloses a process for the preparation of citalopram in which a 4-substituted 2-hydroxymethylphenyl- (4-fluorophenyl) methanol compound is subjected to ring closure and the resulting 5-substituted 1- (4-fluorophenyl) - 1,3-dihydroisobenzofuran is converted to the corresponding 5-cyano derivative which is alkylated with a (3-dimethylamino) propyl halide to obtain citalopram.

Finally, processes for the preparation of the individual enantiomers of citalopram are disclosed in US Pat. No. 4,943,590, from which it can also be seen that the ring closure of the intermediate of formula (III) can be carried out via a labile ester with a base.

It has now surprisingly been found that citalopram can be produced by a new advantageous and safe process using appropriate starting materials. SUMMARY OF THE INVENTION:

Accordingly, the present invention relates to a new process for the preparation of citalopram with the formula (I) 5 AT 005 026 Ul

full:

Converting a compound of formula (VIII)

in which Z is halogen, to a compound of the formula (IV)

HOOC followed by converting the compound of formula (IV) to citalopram.

In particular, the invention relates to such a method, comprising: 6 AT 005 026 Ul (i) reacting the compound of the formula (IV) with a dehydrating agent and a sulfonamide of the formula H2N-SO2-R / in which R: (a) optionally substituted NH2 or C ^ -q-alkyloxy, (b) aryloxy or optionally with halogen, C] __ 4-alkyl, cyano, hydroxy, Ci_4-alkoxy,

Trifluoromethyl, nitro, amino, "4-alkylamino or di-C] __ 4-alkylamino substituted heteroaryloxy or (c) aryl or optionally with halogen, C 1-4 alkyl, cyano, hydroxy, C4.4-alkoxy,

Trifluoromethyl, nitro, amino, C 1-4 alkylamino or di-C 1-4 alkylamino substituted heteroaryl; or (ii) converting the compound of formula (IV) to the corresponding amide of formula (V) NR1R2

wherein R1 and R2 independently represent hydrogen, C 1-6 alkyl, C 1-g alkyl which is substituted with one or more substituents 7 AT 005 026 U1 selected from the group comprising aryl and heteroaryl, hydroxy, C 1-g Are alkoxy, aryloxy, heteroaryloxy, aryl-C 1-6 -alkoxy or trisubstituted silyl, wherein the substituents are independently C] _ g-alkyl, aryl, heteroaryl or aryl-C 1-6 alkyl, and then reacting the amide of the formula ( V) with a dehydrating agent to thereby obtain citalopram as a base or a pharmaceutically acceptable salt thereof.

The conversion of the 5-carboxy derivative of the formula (IV) to the amide of the formula (V) can be carried out using an activated acid derivative of the formula (VI):

wherein R3 is halogen, C] __ g-alkoxy, aryloxy, heteroaryloxy, aryl-C1_g-alkoxy, heteroaryl-C] __ g-alkoxy, alkyl carbonate, aryl carbonate, alkyl carbamate, aryl carbamate, alkyl thiocarbonate, aryl thiocarbonate, alkyl thiocarbamate, arylthyocyloxy, arylthiocyloxy is unsubstituted aryl or substituted or unsubstituted heteroaryl.

In another aspect, the invention relates to processes for the preparation of the intermediate of formula (IV) comprising converting a compound of formula 8 AT 005 026 Ul (VIII) where Z is halogen to the compound of formula (IV).

In yet another aspect, the invention relates to processes for the preparation of the intermediate of formula (VII)

wherein X is selected from halide, CN, OR8 or SR6, wherein R ^ and R6 are independently selected from C ^ g alkyl, aryl, heteroaryl or benzyl and each of these C ^ .g alkyl, aryl, heteroaryl or benzyl groups unsubstituted or with halogen, C 1-4 alkyl, cyano, hydroxy, C 1-4 alkoxy,

Trifluoromethyl, nitro, amino, Ci_4-alkylamino or di-C] __ 4-alky 1 amino is substituted, and NR ^ R ^, wherein R ^ and R8 are independently selected from hydrogen, C ^ -g-alkyl, aryl, heteroaryl or Benzyl and each of these C 1-6 alkyl, aryl, heteroaryl or benzyl groups unsubstituted or with halogen, C1_4-alkyl, cyano, hydroxy, Ci_4-alkoxy,

Trif luormethyl, nitro, amino, C] __ 4-alkylamino or Di-Ci_ 4 -a1ky1ami no is substituted; Y is 0, S or NR9, in which R9 is selected from hydrogen, C 1-6 alkyl, aryl, heteroaryl or benzyl and each of these C 1-6 alkyl, aryl, heteroaryl or benzyl groups is unsubstituted or with halogen, Ci_4-alkyl, cyano, hydroxy, _4-alkoxy, trifluoromethyl, nitro, amino, C4_4-alkylamino or di-Ci_4-alkylamino; 9 AT 005 026 Ul comprehensive

Converting a compound of formula (VIII)

Z

Formula (VIII) NMe2

F wherein Z is halogen to a compound of formula (VII).

In yet another aspect, the present invention relates to an antidepressant pharmaceutical composition comprising citalopram as a base or any convenient salt thereof made by the method of the invention.

Throughout the description and claims, the term " dehydrating agent " any suitable dehydrating agent, and one skilled in the art can easily determine the optimal agent. Examples of suitable dehydrating agents are SOCI2, POCI3, PCI5, SOBr2, POBr3, ΡΒΓς, SOI2, POI3, PI5, P4O30 / oxalyl chloride, carbonyldiimidazole and Vilsmeier reagents. A chlorine-containing agent is preferably used, most preferably SOCI2 or POCI3. Vilsmeier reagents are reagents formed by mixing N, N-dimethylformamide (DMF) and dehydrating agents, examples of which are DMF / SOCI2 and DMF / POCI3. 10 AT 005 026 Ul

Throughout the description and claims, C 1-6 alkyl denotes a branched or unbranched alkyl group having 1 to 6 carbon atoms including, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl- 2-propyl, 2,2-dimethyl-l-ethyl and 2-methyl-l-propyl. Similarly, C] __ 4-alkyl designates such a group having 1 to 4 carbon atoms including, and C ^ -g-alkoxy, C1_4-alkoxy and C] __ 4-alkylamine designate those groups in which the alkyl moiety is as defined above.

Halogen means fluorine, chlorine, bromine or iodine.

In process (i) of the invention, one possible but non-limiting mechanism for the reaction is that the 5-carboxy compound of formula (IV) reacts with the dehydrating agent to form a corresponding activated derivative, which then acts with the sulfonamide, H2N-SO2 -R responds, producing citalopram. A catalytic amount of an acid may be required during the latter reaction.

The sulfonamide used in the process, H2N-SO2-R, is preferably sulfamide, NH2-SO2-NH2.

The optionally substituted NH2 used in the process is preferably tert-butylamine.

The reactions with dehydrating agents in the process of the invention are carried out neat or in a suitable solvent such as sulfolane or acetonitrile. If a solvent is used in the dehydration reaction (11), a catalytic amount of N, N-dimethylformamide may be required. 11 AT 005 026 Ul

In preferred embodiments of the invention, the processes for the preparation of citalopram and / or the compounds of the formula (IV) or (VII) comprise: (a) (VIII)

Implementation of the 5-halogen analog of the formula

where Z is halogen, with Mg or an organolithium compound, e.g. n-BuLi, or with an organometallic complex composed of Mg and / or Mn and / or Li and alkyl or aryl groups, and then with CO2, CS2 or a compound of the formula (IX) X. —A formula (IX)

Y wherein A and X are independently selected from halide, CN, OR- 'or SR8, wherein and R8 are independently selected from C] __ g-alkyl, aryl, heteroaryl or benzyl and each of these C 1-6 alkyl, aryl- , Heteroaryl or benzyl groups unsubstituted or substituted with halogen, C] _. 4-alkyl, cyano, hydroxy, C4_4-alkoxy, trifluoromethyl, nitro, amino, C] __ 4 ~ alkylamino or di-C4_4-alkylamino, and NR7R8, wherein R7 and R8 are independently selected from hydrogen, C] __ 4-alkyl, aryl, heteroaryl or benzyl and each of these C] _ _ g-alkyl, aryl, heteroaryl or benzyl groups is unsubstituted or with halogen, C] _ _4-alkyl , 12 AT 005 026 Ul

Cyano, hydroxy, Ci_4-alkoxy, trifluoromethyl, nitro, amino, Ci_4-alkylamine ° or di-C4-4-alkylamino; Is YO, S or NR9, where R9 is selected from hydrogen, Ci_g-alkyl, aryl, heteroaryl or benzyl and each of these C ^ .g-alkyl, aryl, heteroaryl or benzyl groups unsubstituted or with halogen, C ^^ - Alkyl, cyano, hydroxy, Ci_4-alkoxy, trifluoromethyl, nitro, amino, Ci_4-alkylamino or di-C] L_4-alkylamino; and in the processes for the preparation of citalopram or compounds of formula (IV) followed by reaction with water, a hydroxide such as NaOH, or an aqueous solution of an acid; (B)

Coupling a compound of formula (VIII)

wherein Z is Br or I with an optionally substituted vinyl or acetylene group in the presence of a metal catalyst such as a nickel or palladium-based catalyst, followed by oxidation of the vinyl or acetylene group to carboxy, to thereby obtain the compound of formula (IV) ,

In process (a) are examples of organometallic complexes trialkylmagnesium compounds of the formula (R ^^ MgLi, trialkylmanganese compounds of the formula (R4) 3MnLi and mixed magnesium and manganese complexes of the formula (R4) 3MnMgBr, wherein R4 is Ci_4-alkyl or aryl groups 13 AT 005 026 Ul which may be identical or different. Trialkylmagnesium compounds can be prepared in situ from a Grignard reagent R4MgX (X is halogen) and an organolithium compound, for example n-butyllithium. Trialkylmanganese compounds can be prepared in situ from MnCl2 and an organolithium compound, for example n- (R4) 3MnMgBr can be prepared from a Grignard reagent R4MgX and MnCl2 The starting 5-bromo compound of formula (VIII) can be obtained as described in U.S. Patent 4,136,193.

In process (a) are examples of starting materials of the formula (IX): ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, vinyl chloroformate,

Isobutyl chloroformate, ethyl chlorothiol formate,

Methyl cyanoformate, carbonyldiimidazole and diethyl carbonate. The starting materials of the formula (IX) are commercially available or can be prepared by literature processes.

In process (b), the nickel-based catalyst can be any suitable Ni (0) or Ni (II) containing complex that acts as a catalyst, such as Ni (PPb.3) 3 and (σ-aryl) -Ni (PPh3 ) 2 ^ 1, and the palladium-based catalyst may be any suitable Pd (0) or Pd (II) containing catalyst such as Pd (PPh3) 4, Pd2 (dba) 3 and Pd (PPh) 2Cl2 any suitable agent, such as a peroxide in the presence of a ruthenium catalyst. The starting compounds in which B is a triflate group can be obtained as described in WO00 / 13648. Examples of the vinyl or acetylene groups which are coupled with the compound of formula (VIII) are methyl acrylate, 1-bromobut-1-ene, propyne, trimethyl (prop-1-enyl) stannane, E-1-hexenylboronic acid and prop -1-enyltrifluormethylsulfonat. 14 AT 005 026 Ul

The compound of formula (I) can be used as a free base or as a pharmaceutically acceptable acid addition salt thereof. Such salts which are formed with organic or inorganic acids can be used as acid addition salts. Examples of such organic salts are those with maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylene salicylic acid, methanesulfonic acid, ethane disulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, acetic acid, aspartic acid, mandelic acid, mandelic acid, mandelic acid Stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid,

Benzene sulfonic acid and theophyllic acetic acid as well as the 8-halogen theophylline, e.g. 8-bromo-theophylline.

Examples of such inorganic salts are those with hydrochloric acid, hydrobromic acid,

Sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

The acid addition salts of the compounds can be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water-miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water-immiscible solvent, such as diethyl ether, ethyl acetate or dichloromethane, where the salt separates spontaneously.

The pharmaceutical compositions of the invention can be administered by any suitable route and in any suitable form, e.g. orally in the form of tablets, 15 AT 005 026 Ul

Capsules, powders or syrups, or parenterally in the form of ordinary sterile solutions for injection.

The pharmaceutical formulations of the invention can be prepared by methods conventional in the art. For example, tablets can be produced by mixing the active ingredient with conventional auxiliaries and / or diluents and then compressing the mixture in a conventional tablet machine. Examples of excipients or diluents include: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other auxiliaries or additives, colorants, flavors, preservatives, etc. can be used with the proviso that they are compatible with the active ingredients. Solutions for injections can be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and filling it into suitable ampoules or bottles. Any suitable additive conventionally used in this field can be added, such as tonicity agents, preservatives, oxidation inhibitors, etc.

EXAMPLES

The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. 16 AT 005 026 ul EXAMPLE 1 - 5-Carboxy-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1,3-dihydro-isobenzofuran:

Method (a) - Mg:

A solution of 1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1,3-dihydro-isobenzofuran-5-yl-magnesium bromide in dry THF (90 ml) (prepared by conventional methods from 5-bromo-l - (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1,3-dihydro-isobenzofuran (9 g, 0.024 mol) and magnesium (0.73 g, 0.03 mol)) became dry solid CO2 (50 g) given. After the addition, the mixture was allowed to stand at room temperature for 16 hours.

The volatiles were removed in vacuo and the residue was taken up in water (100 ml). The pH was adjusted to 5.5 by adding HCl (aqueous, 4 N). The aqueous phase was extracted with toluene (10 ml).

The toluene was removed in vacuo and the title compound was obtained as an oil. Yield 6 g.

Process (a) - n-BuLi:

To a solution of 5-bromo-1 ~ (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1,3-dihydro-isobenzofuran (9 g, 0.024 mol) in tert-butyl methyl ether (150 ml) was added n-BuLi (1.6 M in hexane, 40 ml) at -78 to -65 ° C. The temperature of the solution was allowed to rise to -30 ° C over a period of 2 hours. The reaction mixture was added to dry solid CO2 (50 g). After the addition, the mixture was allowed to stand at room temperature for 16 hours. The volatiles were removed in vacuo and the residue was taken up in water (100 ml). 17 AT 005 026 Ul

The pH was adjusted to 5.5 by adding HCl (aqueous, 4 N). The aqueous phase was extracted with toluene (100 ml). The toluene was removed in vacuo and the title compound was obtained as an oil. Yield 7.5 g.

Method (a) - Trialkyl magnesium compound: n-BuLi (20 ml, 1.6 M in hexane) was added to a solution of isopropyl magnesium chloride (8.0 ml, 2 M in diethyl ether) in THF (25 ml) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour, then cooled to -78 ° C and with a solution of 5-bromo-l- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1,3-dihydro -isobenzofuran (5.0 g, 13.0 mmol) in THF (25 ml) was added. The mixture was allowed to warm to -10 ° C over 1 hour, then was cooled again to -78 ° C and CO2 (5.7 g, 130 mmol) was added.

The mixture was allowed to warm to room temperature and then evaporated. Ion exchange chromatography of the residue (Dowex®-50, acid form) and elution with 1 Μ NH3 provided the product as a thick oil. EXAMPLE 2 - 5-Cyano-1- (4-fluorophenyl) -1- (3-dimethylaminopropyl) -1,3-dihydro-isobenzofuran (citalopram, free base) 5-carboxy-1- (4-fluorophenyl) - 1- (3-dimethylaminopropyl) -1,3-dihydro-isobenzofuran (5 g, 0.015 mol) and sulfamide (1.65 g, 0.017 mol) were dissolved in sulfolane (15 ml). Thionyl chloride (2.25 g, 0.019 mol) was added at room temperature and the temperature of the reaction mixture was raised to 130 ° C for 2 hours.

The reaction mixture was allowed to cool to 75 ° C and water (25 ml) was added. The temperature was held at 75 ° C for 15 minutes and then the 18 AT 005 026 Ul

Reaction mixture cooled to room temperature. The pH was adjusted to 9 with ammonium hydroxide and then n-heptane (75 ml) was added. The temperature was raised to 70 ° C and the hot n-heptane layer was isolated, from which the title compound crystallized on cooling. Yield 3.77 g. Purity (HPLC peak area) > 97%. 19

Claims (12)

AT 005 026 Ul CLAIMS: 1. Process for the preparation of citalopram comprising converting a compound of formula (VIII) in which Z is halogen, to a compound of the formula (IV) HOOC 20 AT 005 026 Ul followed by converting the compound of formula (IV) to citalopram. 2. The method according to claim 1, characterized in that (i) the compound of formula (IV) is reacted with a dehydrating agent and a sulfonamide of the formula H2N-SO2-R, wherein R: (a) optionally substituted NH2 or C ^ - g-alkyloxy, (b) aryloxy or heteroaryloxy or (c) aryl or (c) aryl or optionally with halogen, Ci_4-alkyl, cyano, hydroxy, Ci_4 ~ alkoxy, trifluoromethyl, nitro, amino, Ci_4-alkylamino or di-Ci_4-alkylamino Halogen, C] __ 4 ~ alkyl, cyano, hydroxy, C] _. 4-alkoxy, trifluoromethyl, nitro, amino, C] __ 4-alkylamino or di-C] _- 4-alkylamino substituted heteroaryl; or (ii) the compound of the formula (IV) is converted to the corresponding amide of the formula (V): 21 AT 005 026 Ul NR R2 N Formula (V) wherein R1 and R2 are independently hydrogen, C 1-6 alkyl, substituted with one or more substituents selected from the group consisting of aryl and heteroaryl, C] __ g-alkyl, hydroxy, Ci_g-alkoxy, aryloxy , Aryl-C] __ g-alkoxy or trisubstituted silyl, wherein the substituents are independently Οχ_g-alkyl, aryl, heteroaryl or aryl-Cl-g-alkyl, and the amide of formula (V) is then reacted with a dehydrating agent thereby obtaining citalopram as a base or a pharmaceutically acceptable salt thereof. 3. The method according to claim 2, wherein the compound of formula (IV) is reacted with SOCI2 and sulfamide. 4. The method according to claim 3, characterized in that the reaction is carried out in sulfolane. 5. The method according to claim 2, wherein the compound of formula (IV) is reacted with POCI3 and tert-butylamine. 6. The method according to claim 1, characterized in that the compound of formula (IV) is obtained by: 22 AT 005 026 Ul (i) reacting the compound of formula (VIII) Z Formula (VIII) NMe2 F wherein Z is halogen, with Mg or an organolithium compound, e.g. n-BuLi, or with an organometallic complex composed of Mg and / or Mn and / or Li and alkyl or aryl groups to obtain a first intermediate; (ii) subsequent reaction of the first intermediate stage with 002, CS2 or a compound of the formula (IX) Y Formula (IX) wherein A and X are independently selected from halide, CN, OR5 or SR6, wherein R5 and R6 are independently selected from C4_g-alkyl, aryl, heteroaryl or benzyl and each of these C] _ _ g-alkyl -, Aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C] _ .4-alkyl, cyano, hydroxy, 04-4-alkoxy, trifluoromethyl, nitro, amino, C4.4-alkylamino or di-C4_4-alkylamino, and NR7R8, wherein R7 and R8 are independently selected from hydrogen, C1_g-alkyl, aryl, heteroaryl or benzyl and each of these Οχ_g-alkyl, aryl, heteroaryl or 23 AT 005 026 Ul benzyi groups unsubstituted or with halogen, C] __ 4 ~ Alkyl, cyano, hydroxy, Cq__4-alkoxy, trifluoromethyl, nitro, amino, C4.4-alkylamino or di-C4_4-alkylamino; Y is 0, S or NR 9, wherein is selected from hydrogen, C 1-6 alkyl, aryl, heteroaryl or benzyl and each of these C 1-6 alkyl, aryl, heteroaryl or benzyl groups is unsubstituted or with halogen, C ^^ - alkyl, cyano, hydroxy, C] _ "4-alkoxy, trifluoromethyl, nitro, amino, C4,4-alkylamino or di-Cf-4-alkylamino; to get a second intermediate stage; (lii) and then reacting the second intermediate stage with water, a hydroxide, such as NaOH, or an aqueous solution of an acid. 7. The method according to claim 1, characterized in that the compound of formula (IV) is obtained by coupling a compound of formula (VIII) wherein Z is Br or I with an optionally substituted vinyl or acetylene group in the presence of a metal catalyst such as a nickel or palladium-based catalyst, followed by oxidation of the vinyl or acetylene group to carboxy, to thereby obtain the compound of formula (IV) , 24 AT 005 026 Ul 8. Process for the preparation of a compound of formula (IV) HOOC comprising converting a compound of formula (VIII) wherein Z is halogen, to a compound of formula (IV). 9. The method according to claim 8, characterized in that the compound of formula (IV) is obtained by: (i) reacting the compound of formula (VIII) 25 AT 005 026 Ul Z. Formula (VIII) NMe2 F wherein Z is halogen, with Mg or an organolithium compound, e.g. n-BuLi, or with an organometallic complex composed of Mg and / or Mn and / or Li and alkyl or aryl groups to obtain an intermediate; (ii) subsequent reaction of the first intermediate stage with CO2, CS2 or a compound of the formula (IX) Y Formula (IX) wherein A and X are independently selected from halide, CN, OR5 or SR6, wherein R6 and R6 are independently selected from C] __ g-alkyl, aryl, heteroaryl or benzyl and each of these C] _ _ g-alkyl - Aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, C4-4-alkyl, cyano, hydroxy, C ^ _4-alkoxy, trifluoromethyl, nitro, amino, C ^ _4-alkylamino or di-C4_4-alkylamino, and NR7R ^, where R7 and R ^ are independently selected from hydrogen, C] __ g-alkyl, aryl, heteroaryl or benzyl and each of these C] _ _ g-alkyl -, aryl, heteroaryl or benzyl groups unsubstituted or with halogen, C] __ 4-alkyl, cyano, hydroxy, _4-alkoxy, trifluoromethyl, 26 AT 005 026 ul nitro, amino, C] _. 4-alkylamino or di-Cg_4-alkylamino; Y is 0, S or NR ^, wherein R ^ is selected from hydrogen, Cg.g-alkyl, aryl, heteroaryl or benzyl and each of these Cp_5-alkyl, aryl, heteroaryl or benzyl groups is unsubstituted or with halogen, Cp. .4-alkyl, cyano, hydroxy, Cp_4 ~ alkoxy, trifluoromethyl, nitro, amino, Ci_4-alkylamino or di-C4_4-alkylamino; to get a second intermediate stage; (iii) and then reacting the second intermediate stage with water, a hydroxide, such as NaOH, or an aqueous solution of an acid. 10. The method according to claim 8, characterized in that the compound of formula (IV) is obtained by coupling a compound of formula (VIII) wherein Z is Br or I with an optionally substituted vinyl or acetylene group in the presence of a Menall catalyst, such as a nickel or palladium-based catalyst, followed by oxidation of the vinyl or acetylene group to carboxy, to thereby obtain the compound of formula (IV) , 11. Process for the preparation of a compound of formula (VII) 27 AT 005 026 Ul wherein X is selected from halide, CN, OR5 or SR6, wherein R ^ and R6 are independently selected from C] __ g-alkyl, aryl, heteroaryl or benzyl and each of these C] __ g-alkyl, aryl, heteroaryl or benzyl groups unsubstituted or substituted with halogen, Ci_4-alkyl, cyano, hydroxy, C] __ 4-alkoxy, trifluoromethyl, nitro, amino, Cg_4-alkylamino or di-C4_4-alkylamino, and NR7R8, wherein R7 and R8 are independently selected from hydrogen , C] __ g-alkyl, aryl, heteroaryl or benzyl and each of these C] _ _ g-alkyl -, aryl, heteroaryl or benzyl groups unsubstituted or with halogen, C4_4-alkyl, cyano, hydroxy, C4_4-alkoxy, trifluoromethyl, Nitro, amino, C4_4-alkylamino or di-C4_4-alkylamino is substituted; Is YO, S or NR ^, wherein R ^ is selected from hydrogen, C4_g-alkyl, aryl, heteroaryl or benzyl and each of these C4_g-alkyl, aryl, heteroaryl or benzyl groups is unsubstituted or with halogen, Cf-4-alkyl, cyano , Hydroxy, C4_4-alkoxy, trifluoromethyl, nitro, amino, C4_4-alkylamino or di-Cf-4-alkylamino; comprising converting a compound of formula (VIII) 28 AT 005 026 Ul wherein Z is halogen, to a compound of formula (VII). 12. The method according to claim 11, characterized in that the compound of formula (VII) is obtained by: (i) reacting the compound of formula (VIII) where Z is halogen, with Mg or an organolithium compound, e.g. n-BuLi, or with an organometallic complex composed of Mg and / or Mn and / or Li and alkyl or aryl groups to obtain a first intermediate; 29 AT 005 026 Ul (ii) then reacting the first intermediate stage with CO2, CS2 or a compound of the formula (IX) Y Formula (IX) wherein A and X are independently selected from halide, CN, OR5 or SR6, wherein R5 and R6 are independently selected from C 1-6 alkyl, aryl, heteroaryl or benzyl and each of these C 1-5 alkyl , Aryl, heteroaryl or benzyl groups are unsubstituted or substituted with halogen, Ci_4-alkyl, cyano, hydroxy, 04-4-alkoxy, trifluoromethyl, nitro, amino, C1_4-alkylamino or di-04.4-alkylamino, and NR7R8, where R7 and R8 are independently selected from hydrogen, Ci_g-alkyl, aryl, heteroaryl or benzyl and each of these alkyl, aryl, heteroaryl or benzyl groups unsubstituted or with halogen, 04.4-alkyl, cyano, hydroxy, C4-4-alkoxy, Trifluoromethyl, nitro, amino, 04.4-alkylamino or di-C4.4-alkylamino is substituted; YO, S or NR9, wherein R9 is selected from hydrogen, C4_g-alkyl, aryl, heteroaryl or benzyl and each of these C4_g-alkyl, aryl, heteroaryl or benzyl groups is unsubstituted or with halogen, 04-4-alkyl, cyano , Hydroxy, 04.4-alkoxy, trifluoromethyl, nitro, amino, C4.4-alkylamino or D1-C4_4-alkylamino; to obtain the compound of formula (VII). 30